Lung cancer is the leading cancer killer worldwide accounting for 1.37 million deaths annually. In the United States, lung cancer causes more deaths than the next three most common cancers combined (colon, breast and pancreatic) and in 2014, an estimated 159,260 Americans will die from lung cancer. Lung cancer arises as a result of environmental exposures, such as smoking, combined with genetic alterations such as deregulation of oncoproteins, including Myc and RAS, and loss of tumor suppressors, such as p53. The vast majority of patients that develop lung cancer will have non-small cell lung cancer (NSCLC), and 50% of patients will initially present with advanced NSCLC, which is incurable using currently available therapies. The median survival of patients with advanced NSCLC treated with chemotherapy is 8-10 months.
A major therapeutic goal in lung cancer is to identify agents against targets that are critical to the growth of lung cancers. This has been clinically achieved for patients that harbor activating mutations in EGFR or chromosomal translocations such as EML4-ALK using selective ATP-competitive kinase inhibitors. Unfortunately the duration of response to targeted kinase inhibitors is typically less than 2 years, and most lung tumors do not express an oncogene that is targeted by an available drug. For example, loss of p53 is a common event in lung cancer, but there are currently limited drugs that can exploit its loss.
Phosphatidylinositol 4,5-bisphosphate (PIP2) is a membrane bound lipid molecule with the ability to affect a wide array of signaling pathways that regulate different cellular processes (Camilli et al., Science, 1996, 271: 1533-1539). PIP2 is used as a precursor to generate the second messengers PIP3, DAG, and IP3, indispensable molecules for signaling events generated by membrane receptors. However, PIP2 can also directly regulate a vast array of proteins and is emerging as a crucial messenger with the potential to distinctly modulate biological processes critical for both normal and pathogenic cell physiology (Martin, T. F. J. (1998) Annu. Rev. Cell Dev. Biol. 14, 231-264). PIP2 directly associates with effector proteins via unique phosphoinositide binding domains, altering their localization and/or enzymatic activity. The spatial and temporal generation of PIP2 synthesized by the phosphatidylinositol phosphate kinases (PIPKs) tightly regulates the activation of receptor signaling pathways, endocytosis and vesicle trafficking, cell polarity, focal adhesion dynamics, actin assembly, and 3′ mRNA processing (Balla et al., Phosphoinositides I: Enzymes of Synthesis and Degradation, 2012, Chapter 2, PIP Kinases from the Cell Membrane to the Nucleus, p 25). Two types of PIP kinases have been identified, type I and type II PI(4)P 5-kinases (Fruman et al., Annu. Rev. Biochem., 1998, 67: 481-507). Type I phosphorylates PI(4)P at the 5-position to make PI(4,5)P2 and type II can phosphorylate PI(5)P and PI(3)P at the 4-position to make PI(4,5)P2 and PI(3,4)P2.
Recently, it has been discovered that RNAi-mediated depletion of two type II PIP kinases, PIP4K2A and PIP4K2B, selectively inhibited the proliferation of TP53 mutant breast cancer cell line (BT474 cells) while cells that were wild-type for TP53 were unaffected (Emerling et al., Cell, 2013, 155: 844-857). These kinases phosphorylate the lipid phosphatidylinositol-5-phosphate (PI-5-P) at the 4-position of the inositol ring to generate phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) and are in the same kinase family as the PI3 kinases which are now targeted by a number of clinical stage drugs. Genetic studies in mice demonstrate that homozygous germline deletion of PIP4K2B results in healthy mice with a normal life span, while combined deletion of PIP4K2B and TP53 results in early embryonic lethality (FIG. 1) (Rameh et al., Nature, 1997, 390: 192-196). Mice expressing one allele of PIP4K2B and homozygous deletion of PIP4K2A and TP53 are viable and exhibit a dramatic reduction in cancers and an extended lifespan compared to their littermates that were TP53 deleted with wild type PIP4K2A. These studies suggest that PIP4K2A/B becomes essential when TP53 function is lost. Therefore, small molecule inhibitors of PIP4K2A/B may hold promise as a therapeutic agent for treating cancer.